DESCRIPTION: The overall goal of this program of research is to develop new tactics and strategies to synthesize alkaloid natural products and other biologically-active nitrogen containing compounds. Within this context a number of specific objectives have been established, and these may be divided into methodological studies and the total syntheses of biologically active alkaloids and related compounds. On the methodological front, the principal goals are to: (1) examine cycloaddition reactions, especially Diels-Alder reactions involving heterodienes or vinylogous imides, to construct heterocyclic structural subunits found in alkaloids; (2) investigate ring-closing metathesis as a method for forming unsaturated nitrogen heterocycles; (3) expand the scope and synthetic utility of vinylogous Mannich reactions that involve inter- and intramolecular reactions of iminium salts with nucleophilic partners, especially oxygenated furans; and (4) explore 1,2-metallate rearrangements as a novel entry to unsaturated nitrogen compounds. In the arena of total synthesis, the PI is to: (1) apply intramolecular hetero Diels-Alder reactions in tandem with biomimetic chemistry to synthesize complex indole alkaloids of the Strychnos, Ajmaline, and Sarpagine families including the glycine receptor antagonist strychnine, condylocarpine, polyneuridine, quebrachidine and the anesthetic agent akuammidine; (2) complete a convergent asymmetric synthesis of the anticancer agent manzamine A using a strategy that features an intramolecular (4+2) cycloaddition of a vinylogous imide and ring-closing metathesis reactions; and (3) develop a general approach to alkaloids containing butyrolactone and piperidine subunits exploiting novel vinylogous Mannich additions as key constructions and demonstrate the broader efficacy of this strategy by applying it to concise syntheses of Stemona alkaloids including the insecticidal and antitussive agent croomine and the related alkaloid stemoamide, the neuroactive Ergot alkaloid methyl lysergate, the sodium channel activator pumiliotoxin 251 D, and the angiotensin converting enzyme inhibitor A58365A. It is intended to prepare reasonable quantities of the targeted compounds and selected intermediates for submission to C. P. Starks, Inc., Eli Lilly, Merck and Abbott Laboratories for biological evaluation.